Most events occur in environments that are rich with visual, auditory, tactile and olfactory stimuli. Animals must assimilate vast amounts of information to learn about important, behaviorally relevant events. Complex or configural associative learning is that which requires the formation of inter-relationships among different, simultaneously presented stimuli. This type of learning has traditionally been considered to occur within cortico-hippocampal networks in the brain, but the particular pathways and regions that encode this essential form of learning are unresolved. The overarching hypothesis of this research is that the retrosplenial cortex (RSP) and its connections with the postrhinal cortex are critical for configural associative learning. Together, these aims are designed to investigate the neural activity, functional circuitry and specific contribution of RSP to behavior. The experiments in Aim 1 pose the question: Is RSP an active mediator of learning? Neuronal activation in RSP will be measured in rats following contextual fear conditioning (a form of configural associative learning). Behaviorally-induced neural activity will be assessed by quantifying the sub-region specific expression of the immediate early gene, Arc (activity related cytoskeletal protein), which has been shown to play a prominent role in synaptic plasticity. These studies have the potential to establish that RSP is a mediator, rather than simply a conduit, of sensory information during associative learning. Specific Aim 2 is focused on understanding which subregions of RSP communicate with other cognitive brain regions when an animal is learning. For these studies, retrograde tracing will be combined with immediate early gene expression to identify RSP pathways that are most prominently activated following aversive fear conditioning. In aim 3, the negative patterning task, which is the demonstrative test of configural learning, will be employed to explicitly test the hypothesis that RSP is necessary for associative learning that involves the processing of multiple, simultaneously presented stimuli. This proposal addresses basic questions about the neural basis of cognition in RSP, a brain region that is closely associated with pathological conditions such as Alzheimer's disease and Schizophrenia. Elucidating the neural pathways involved in learning in healthy brains could prove to be especially useful in identifying target regions that may be most affected in neurodegenerative and psychological disorders of cognitive function. PUBLIC HEALTH RELEVANCE: This project has the potential to produce critical new insights about the neural organization underlying learning and memory. By investigating a brain region (the retrosplenial cortex) that is known to be compromised in human disorders such as Alzheimer's disease and schizophrenia, this work may eventually lead to the development of novel therapies and treatments for some of the most pervasive human disorders.